Description: (Verbatim from the applicant's abstract) The goal of the research proposed here is the development of a new theoretical approach for the modeling of transmembrane [TM] alpha-helical domains (excluding surface loops) of membrane proteins using energy minimization and experimental data. The global energy minimization procedure will include two parts that quantitatively describe (1) formation of TM alpha-helices and alpha-hairpins in a flexible molten globule-like state within the lipid bilayer, and (2) stepwise association of the alpha-helices and alpha-hairpins into larger alpha-bundles. This method is an extension of our previously developed thermodynamic model of secondary structure that describes formation of alpha-helices in micelle-bound peptides and water-soluble proteins. The packing of TM helices will provide the energetically optimal clustering of polar, aromatic and sulfur-containing groups within the alpha-bundle and the "outside" arrangement of aliphatic and aromatic side-chains that preferentially interact with lipid tails and headgroups, respectively. The intrinsic stabilities and interaction energies of the helices will be calculated using published mutagenesis-derived delta delta G energies, experimental transfer energies of model compounds, calculations of contact surfaces, and a set of adjustable solvation constants. The method will be extensively tested for water-soluble and transmembrane alpha-bundles with known 3D structure, and then applied for membrane proteins with 5-8A resolution electron microscopy data available.